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Title: Functional genomics approaches to understanding heterogeneous tissues in health and disease
Author: Handel, Adam E.
ISNI:       0000 0004 6497 7152
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Functional genomics approaches offer an unparalleled window into cellular biology. It is particularly challenging to apply these methods to heterogeneous tissues, in which multiple cell types or transcriptomic identities co-exist. I applied single cell and bulk functional genomics approaches in an attempt to understand aspects of the biology underlying cerebral cortex and thymic epithelial cells. These are both extremely heterogeneous tissues but the nature of the heterogeneity differs: in cortex there are a large number of different cell types, whereas in thymic epithelial cells, despite a limited number of cell types, individual cells express virtually every gene in the transcriptome. In Chapter 1, I provide a general overview of the currently available functional genomics tools and briefly review relevant aspects of cortical and thymic biology. The first three results chapters examine functional genomics approaches to cerebral cortex. Chapter 2 details the application of single cell functional genomics techniques to examine the extent to which stem cell-derived cortical neurons resemble primary human cortical neurons. In Chapter 3, I use RNA sequencing in cortical neurons derived from wild-type or PSEN1 mutant stem cells in an attempt to identify an Alzheimer's disease-relevant gene signature and to assess how much variability there is between batches of stem cell differentiation. Chapter 4 applies DNase-seq footprinting to primary brain tissue in order to understand how common variants associated with altered gene expression or susceptibility to neurological disease might exert their effects. The last two results chapters focus on thymic epithelial cells. In Chapter 5, I integrate multiple functional genomics datasets to identify a set of genes targeted by Foxn1, a criticial transcription factor in thymus development and function. Chapter 6 use single cell RNA-seq from mature medullary thymic epithelial cells to gain an insight into how promiscuous gene expression in the thymus is orchestrated at the level of individual cells. Finally, in Chapter 7, I summarise the implications of my findings for cortical and thymic biology and speculate on the potential directions that functional genomics may take in the future to better understand heterogeneous tissues.
Supervisor: Ponting, Christopher ; Cader, Zameel ; Holländer, Georg Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available